JP7156945B2 - Galenic preparations of organic compounds - Google Patents

Description

The present invention is a solid unit oral dosage form comprising a 1:1 molar ratio of Sacubitril and Valsartan, preferably in the form of the so-called Angiotensin Receptor Neprilysin Inhibitor (ARNI) LCZ696, which requires low amounts and individual dosing. or a solid unit oral dosage form of sacubitril, valsartan and a sodium ion complex hydrate suitable for use in children or other patients who encounter swallowing problems, e.g., as a result of disease or due to advanced age, said solid Embodiments of the invention relate to the manufacture of dosage forms, as well as to therapy using said dosage forms.

LCZ696: Sacubitril (AHU377, (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester, prodrug of NEP inhibitor) N-(3-Carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester; IUPAC name 4-{[(1S,3R)- 1-([1,1′-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoic acid) is a known angiotensin receptor blocker (ARB) Together with valsartan, it forms a sodium salt hydrate complex known as LCZ696, containing the anionic forms of sacubitril and valsartan, the sodium cation, and a water molecule, respectively, in a molar ratio of 1:1:3:2.5 (solid (6:6:18:15 ratio within the cell of the asymmetric unit of the crystal) and is represented schematically by the following formula:

Said conjugate is also referred to by the following chemical name: Trisodium [3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S) -3′-methyl-2′-(pentanoyl{2″-(tetrazol-5-ylato)biphenyl-4′-ylmethyl}amino)butyrate]hemipentahydrate, or octadecanodium hexakis(4-{[( 1S,3R)-1-([1,1′-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate)hexakis(N-pentanoyl- N-{[2′-(1H-tetrazol-1-id-5-yl)[1,1′-biphenyl]-4-yl]methyl}-L-valinate), water (1/15) (IUPAC nomenclature law).

Ingestion of LCZ696 resulted in a 1:1 molar ratio of (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid, the active form of LBQ657. ), and valsartan, which inhibits the type 1 angiotensin II (AT1) receptor, results from systemic exposure becomes.

Combinations of sacubitril and valsartan, in particular LCZ696 and formulations thereof, have been previously disclosed in WO2003/059345, WO2007/056546 and WO2009/061713, which are incorporated herein by reference.

Mode of Action: Inhibition of neprilysin results in high levels of bioactive natriuretic peptides (NP), including atrial natriuretic peptide (ANP). NPs mediate these cardiovascular effects via activation of the A-type natriuretic peptide receptor (NPR-A) and their second messenger cyclic GMP (cGMP), resulting in potent vascular dilation, natriuresis, diuresis, inhibition of the renin-angiotensin-aldosterone system (RAAS) by reducing renin and aldosterone release, decreased sympathetic drive, and anti-proliferative and anti-hypertrophic properties in vascular endothelial and smooth muscle cells have the effect of Angiotensin receptor blocker (ARB) components provide AT1 receptor antagonism and prevent the adverse effects of angiotensin II, thereby reducing peripheral vascular resistance. By delivering dual effects and potentially complementary beneficial effects, LCZ696 may offer clinical utility for patients with cardiovascular and renal disease.

Various uses of combinations of sacubitril and valsartan, particularly LCZ696, for the treatment of patients with various cardiovascular and/or renal diseases are described in WO2003/059345, WO2007/056546, It is described in WO2012/027237, WO2014/029848, WO2015/030711 and WO2015/028941.

In particular, inhibition of neprilysin (NEP) with long-term oral administration of LCZ696 exacerbates heart failure (HF) by enhancing the activity of natriuretic peptides secreted by the heart in response to increased cardiac load and intravascular volume. can promote the body's intrinsic ability to compensate for LCZ696 provides concomitant inhibition of NEP and type 1 angiotensin (AT1) receptors, unlike any other therapy for HF. NEP inhibition via renin-angiotensin-aldosterone system (RAAS) inhibition and consequent increase in natriuretic peptide (NP) activity by AT1 receptor blockade complements the cardiovascular (CV) system to benefit HF patients. have a positive effect.

PARADIGM-HF (CLCZ696B2314; N=8442) In a pivotal phase 3 trial in adult patients with HF with reduced ejection fraction (HFrEF), LCZ696 initially met the composite endpoint of death from CV or hospitalization from HF. superior to enalapril (standard of care) with a relative risk reduction (RRR) of 20% (p=0.0000002) in delaying the time to onset of In addition, LCZ696 was associated with a 20% RRR in delaying time to death from CV (p=0.00004) and a 21% RRR in delaying time to first hospitalization from HF (p=0.00004). 0.00004) and was superior to enalapril. PARADIGM-HF also showed that LCZ696 is generally safe and well tolerated in adult patients with HF (McMurray et al, 2014).

LCZ696 is now considered for use in children as an alternative to currently available therapies for cardiovascular diseases such as heart failure (HF).

Congenital heart disease and cardiomyopathy are the two most common causes of childhood HF. Incidence of 10.4% in HF patients younger than 16 years with congenital or acquired heart disease, and an incidence of HF of 2-7.7 per 100,000 in the entire pediatric population has been reported. Infants between the ages of 0 and 4 years have the highest incidence of HF. A second peak in childhood HF appears between the ages of 10 and 18, primarily due to cardiomyopathy and irreversible congenital heart defects or palliative recovery of congenital heart defects. It is estimated that between 12,000 and 35,000 children under the age of 19 are diagnosed with childhood HF in the United States each year. The highest HF burden comes from children born with congenital malformations. Congenital heart disease occurs in approximately 8 per 1,000 births and 1-2 per 1,000 develop HF. A wide variety of congenital anomalies can be present. Most of these children are diagnosed before the age of one and many undergo surgical intervention early, usually before the age of two.

Another major cause of childhood HF is cardiomyopathy. At any given time, cardiomyopathy affects at least 100,000 children worldwide. Recent studies show that the annual incidence of cardiomyopathy is similar to approximately 1 per 100,000 children under the age of 18 in the United States, Australia, United Kingdom and Ireland. The highest incidence is in children under 1 year of age. Dilated cardiomyopathy (usually diagnosed as idiopathic, familial, or myocarditis) is the most common type. In the United States, the annual incidence of dilated cardiomyopathy in children under the age of 18 is approximately 0.57 cases per 100,000 person-years. Familial isolated cardiomyopathy, hypertrophic cardiomyopathy due to congenital metabolic disorders or malformation syndromes are the next most common types. Cardiomyopathy can also be associated with muscular dystrophy, such as Duchenne muscular dystrophy and myotonic dystrophy. Other types of cardiomyopathy are less common, including restrictive cardiomyopathy and arrhythmic cardiomyopathy. In 41-63% of cases of cardiomyopathy, diagnosis is made within the first year of life, usually by symptoms of HF. The morbidity and mortality of these diseases are high and they are the most common cause of heart transplantation in children over the age of one year. Nearly 40% of children with symptomatic cardiomyopathy either receive a heart transplant or die by age two.

Notably, no other drug trials to date have demonstrated the usefulness of any drug therapy outcome in children with HF. Due to efficacy and safety studies of LCZ696 in children, there is a need for suitable formulations to enable pediatric studies and subsequent pediatric treatment. Such formulations suitable for pediatric patients may also be suitable for other patients who encounter swallowing problems, for example, as a result of disease or old age, or for psychological reasons.

A liquid dosage form may allow for individualized and facilitated delivery to the patient by swallowing, but as noted chemical and physical stability and hence storage and transport of LCZ696, especially complex The stability of the body, especially the prodrug sacubitril, can be hindered in liquids, the excipient tolerance can be a source of limitation, and flavor considerations can lead to dissolved or dispersed forms in liquid formulations. It can be difficult to supply drugs in

On the other hand, conventional solid oral dosage forms, ie, tablets and capsules for adult patients and/or those to whom standard adult dosages are to be administered, can be said to have poor swallowability and dosing adaptability.

Small particle solid dosage forms such as powders, granules, agglomerates or pellets (e.g. obtained from a fluidized bed or other manufacturing process), minicapsules or uncoated tablets are, in principle, subject to dosage flexibility. Although it may be possible to meet the requirement for , however, consideration of taste-masking issues applies to many of these variants, and administration with food may reduce the ingestion of the drug for children and other patients. It can be difficult to implement when it is considered more attractive and likable.

Currently marketed LCZ696 (trade name ENTRESTO™) is available in oral dosage form as 200 mg, 100 mg and 50 mg immediate release film-coated tablets. This formulation does not meet the requirements of a pediatric formulation in terms of strength, dosing compatibility, patient acceptability (eg swallowability) and size.

Also, the physico-chemical properties, especially the stability of the prodrug Sacubitril, and to a lesser extent the flavor of the drug substance, hinder the development of liquid oral formulations that are standard in pediatric treatments.

A dosage form sometimes considered for pediatric use is a formulation in the form of a minitablet, which can be provided with or without a small amount of soft food such as pudding or applesauce. However, the very small size of these tablets of a few mg makes the process of producing tablets with uniform content at the individual mini-tablet level as described in WO 2010/086312 particularly difficult. there is a possibility. Moreover, not all pharmacopoeial methods defined for medicines are suitable for mini-tablets. To date, mini-tablets have not been described in any pharmacopeia monograph.

In addition, the chemistry of LCZ696 as a salt complex should prevent premature release and dissolution of the drug when mixed in food while still allowing an immediate release profile upon ingestion.

In particular, the release profile of the pediatric formulation must also demonstrate bioequivalence to the already available film tablets of LCZ696 at dose strengths of 50 mg, 100 mg and 200 mg at the appropriate overall dosage.

Thus, in terms of pediatric administration, there is still an unmet need to develop and provide a pediatric formulation of LCZ696 that addresses the shortage of commercially available film-coated tablets, whereby said formulation is marketed. It has the size, dosing adaptability, acceptability and palatability desired for administration to children and other patients, as described above, while maintaining bioavailability comparable to drug products.

Surprisingly, despite the technical difficulties and formulation constraints of LCZ696, the known technical requirements of the state of the art, particularly with the adaptation of the preferred method, are the present invention in the production of mini-tablets. which overcomes the problem and is a solid unit of sacubitril and valsartan in a 1:1 molar ratio for oral administration in the form of mini-tablets having a core and an outer coating of Made it possible to offer dosage forms:
- the core of said tablet comprises, as active ingredient, preferably in the form of LCZ696, a therapeutically effective amount of Sacubitril and Valsartan in a molar ratio of 1:1; and at least one pharmaceutically acceptable excipient;
- the outer coating is in the form of a slow-release and/or protective film coating, which optionally also has taste-masking properties, in particular the film-coating is slow-release, for foods that are mixed before administration has the functionality of

In one embodiment, the effective amount of active ingredient is between about 2 mg and about 5 mg per mini-tablet, corresponding to a 1:1 molar ratio of Sacubitril (free acid) and Valsartan (free acid) loadings, respectively. .

In another embodiment, said mini-tablets are between 1 mm and 4 mm in size.

Accordingly, in one aspect, the present invention relates to solid unit dosage forms for oral administration in the form of mini-tablets having a core and outer coating of:
- the core comprises as active ingredients a therapeutically effective amount of Sacubitril and Valsartan in a molar ratio of 1:1; and at least one pharmaceutically acceptable excipient;
wherein the effective amount of active ingredient is between about 2 mg and about 5 mg per mini-tablet, corresponding to a 1:1 molar ratio of valsartan (free acid) and sacubitril (free acid), respectively;
- the outer coating is in the form of a slow release and/or protective film coating,
- the size of the mini-tablets is between 1 mm and 4 mm;

In one embodiment, the active ingredient is trisodium [3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate, as described in more detail above in the introduction -(S)-3′-methyl-2′-(pentanoyl{2″-(tetrazol-5-ylate)biphenyl-4′-ylmethyl}amino)butyrate]hemipentahydrate (LCZ696) .

In one aspect, the mini-tablets are provided with a dispenser for ease of dosing and administration.

In one aspect, the mini-tablets are provided in a container such as a capsule. Such capsules contain a defined number of mini-tablets according to the invention. said number can be selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20; Preferably the container, preferably the capsule, contains 4 or 10 mini-tablets.

In one aspect, the invention also relates to methods for making the solid oral dosage forms described herein.

In another aspect, the present invention provides a 1:1 molar ratio of Sacubitril and Valsartan, especially in the form of LCZ696, for oral administration in the form of coated mini-tablets, for use as an age-appropriate pediatric formulation. , which meets technical, dosing and pharmacokinetic requirements.

In another aspect, the present invention provides the mini-tablets described herein for use in the treatment of diseases or conditions in the pediatric population, particularly in the treatment of heart failure in patients belonging to the pediatric population. provides a solid unit dosage form of sacubitril and valsartan in a 1:1 molar ratio for oral administration.

However, the use of the solid unit dosage form according to the present invention is not limited to administration to children, but generally patients who have difficulty swallowing due to, for example, disease or age of the patient, or LCZ696, which is marketed due to psychological fetters. can be used in patients with limited ability to orally ingest tablets of Thus, in a further aspect, the present invention relates to chronic heart failure, hypertension, angina pectoris, myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiomyopathy, renal failure, peripheral vascular disease, left ventricular hypertrophy, It relates to the use of the solid oral dosage forms described herein in the treatment or prevention of cognitive impairment and stroke, particularly in patients requiring low and discrete medications or experiencing swallowing problems.

Additional features and advantages of the present disclosure will become apparent from the detailed description of the invention that follows.

Definition:
Throughout this specification and the claims that follow, the following terms are defined with the following meanings, unless explicitly stated otherwise. The following definitions may be used independently to provide more specific variations of one or more or (as far as possible) all generic terms used above or below, thus defining a more specific invention. Embodiments can be defined.

The term "prevention" refers to prophylactic administration to a healthy subject to prevent the development of the conditions mentioned herein. Furthermore, the term "prevention" refers to prophylactic administration to patients who are in a pre-stage of the condition to be treated.

The term "treatment" is understood to be the management and therapy of a patient aimed at combating a disease, condition or disorder.

The term "effective amount" or "therapeutically effective amount" refers to a drug or drug that elicits a desired biological and/or medical response in a tissue, system or animal (including humans) being sought by a researcher or clinician. It refers to the amount of therapeutic agent. In particular, the terms "effective amount" or "therapeutically effective amount" are those that halve or reduce the progression of the condition being treated, or otherwise completely or partially cure the condition, e.g., chronic heart failure. Refers to the amount of active ingredient or drug that cures or alleviates.

The term "patient" includes, but is not limited to, humans, dogs, cats, horses, pigs, cows, monkeys, rabbits and mice. Preferred patients are humans.

The terms "administration of" and/or "administering" a compound provide a compound of the invention or a pharmaceutically acceptable salt or ester thereof, or a prodrug thereof, to a subject in need of treatment. should be understood to mean Administration of the compositions of the invention to practice this method of therapy is accomplished by administering a therapeutically effective amount of the compounds in the composition to a subject in need of such treatment or prevention. The need for prophylactic administration according to the methods of the invention is determined using known risk factors. The effective amount of an individual compound will ultimately be determined by the attending physician, but will be selected based on factors such as the precise disease being treated, the severity of the disease, and other diseases or conditions the patient is suffering from. It will depend on the route of administration, other drugs and treatments that the patient may require concurrently, and other factors at the discretion of the physician.

As used herein, the term "about" refers to ±20%, ±10%, ±5% or ±2% of a value.

The term "pharmaceutically acceptable" as used herein means, within sound medical judgment, suitable for contact with tissue of mammals, especially humans, and without excessive toxicity, irritation, or excessive toxicity. refers to those compounds, substances, compositions and/or dosage forms without the complexity of , allergic reactions, and other problems commensurate with a reasonable benefit/risk ratio.

As used herein, the term "release" refers to the process of bringing an oral pharmaceutical dosage form into contact with a liquid, which causes movement of drug outside the dosage form into the liquid surrounding the dosage form. The combination of delivery rate and duration exhibited by a given dosage form in a patient can be described as its in vivo release profile. The release profile of a dosage form can exhibit different rates and durations of release and can be sustained. Sustained release profiles include release profiles in which one or more active ingredients are released over a period of time, either at a constant rate or a variable rate.

For the purposes of this application, an immediate release formulation is a formulation that exhibits release of the active substance, which is not intentionally altered by a particular formulation design or manufacturing process.

For the purposes of this application, a "sustained release formulation" is a formulation that exhibits release of an active substance, which is deliberately controlled (altered) by a particular formulation design or manufacturing process. This sustained release can typically be obtained by delaying the release time of the active ingredient. Typically, for the purposes of the present invention, sustained release refers to release that is delayed for 30-60 minutes.

As used herein, the term "disintegration" refers to the process by which an oral pharmaceutical dosage form is broken into discrete particles and dispersed, typically with a liquid. If a solid oral dosage form is present, any residue of the solid oral dosage form other than the insoluble coating or capsule shell fragments remaining on the screen of the tester is an apparent hard core according to United States Pharmacopeia <701>. Disintegration is achieved when it is in a state of being a soft mass with no The liquid for determining disintegration properties is water, such as tap water or deionized water. Disintegration time is measured by standard methods known to those skilled in the art, but see the harmonization procedures given in US Pharmacopoeia <701> and European Pharmacopoeia 2.9.1 and Japanese Pharmacopoeia.

As used herein, the term "dissolve" or "dissolve" refers to a solid substance, particularly the active ingredient herein, which is dispersed in molecular form in a medium and transparent when no other opaque substance is present. refers to the process of becoming a solution of The dissolution rate of the active ingredient of the oral pharmaceutical dosage form of the present invention is the amount of drug substance that goes into solution per unit time (in the context of the present invention, under standard conditions of liquid/solid interface, temperature and solvent composition). measured separately or together as sacubitril and/or valsartan). Dissolution rates are measured by standard methods known to those of skill in the art, but see harmonization procedures given in US Pharmacopoeia <711> and European Pharmacopoeia 2.9.3 and Japanese Pharmacopoeia. For the purposes of the present invention, tests to determine the dissolution of individual active ingredients are performed according to United States Pharmacopoeia <711> at pH 6.8 using a paddle stirrer at 50 rpm (revolutions per minute). be done. The dissolution medium is preferably a buffer, typically a phosphate buffer at pH 6.8, such as 900 mL of 0.05 M phosphate buffer at pH 6.8. Alternatively, tests to determine dissolution of individual active ingredients are performed according to US Pharmacopeia <711> at pH 2.0 using the paddle method at 50 rpm (revolutions per minute). The dissolution medium is typically 900 mL of 0.01N HCl at pH 2.0, 37±0.5° C., which is also a buffering agent, typically a phosphate buffer, especially pH 2. 0.0, 37±0.5° C. at a molar concentration of 0.1 M. Alternatively, tests to measure dissolution of individual active ingredients are performed according to US Pharmacopeia <711> at pH 4.5 using a paddle stirrer at 50 or 75 rpm as specified. The dissolution medium is preferably a buffer, typically a phosphate buffer (eg 900 ml or 1000 mL of pH 4.5 phosphate buffer). All dissolution tests are performed at the temperature indicated, specifically 37±0.5°C.

The term "mini-tablet" within the scope of this application means that the total weight in uncoated form is approximately 2-30 mg, such as approximately 4-9 mg, such as approximately 7 mg, and in coated form approximately 2.2 mg. A small tablet is shown that is ˜32 mg, such as approximately 4.1-10 mg, such as approximately 7.1-7.5 mg.

Mini-tablets are a specific form of multiparticulates as defined herein. These include preparations from other smaller multiparticulates such as particles, granules or beads, and can be prepared as described herein. mini-tablets are, for example, circular, for example about 1.25-3 mm in diameter, or as otherwise defined herein; cylindrical, for example, having a convex upper surface and a convex lower surface; For example, cylindrical diameter and height of 1-3 mm independently of each other, or as defined elsewhere herein; It may have any shape for tablets known to those skilled in the art, such as 25-3 mm, or as otherwise defined herein.

As used herein, the term "1:1 molar ratio of Sacubitril and Valsartan" refers to a therapeutically effective amount of a 1:1 molar ratio of (i) Valsartan or a pharmaceutically acceptable salt thereof; and (ii) Sacubitril. or a pharmaceutically acceptable salt thereof,
In particular, the combined sodium salt complex trisodium [3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3′-methyl -2′-(pentanoyl{2″-(tetrazol-5-ylate)biphenyl-4′-ylmethyl}amino)butyrate]hemipentahydrate (LCZ696), and in the forms defined in more detail below, compounds comprising The term "sacubitril and valsartan in a 1:1 molar ratio" also includes valsartan and sacubitril and links them together via a non-covalent or covalent bond, optionally via a linker. It can refer to a body or compound.

embodiment
Size and form: In one embodiment of the invention there is provided a solid unit dosage form in the form of mini-tablets as described herein above, said mini-tablets having a diameter of 1 mm to 3 mm, especially 1.25 mm to 2.5 mm. 75 mm, but especially between 1.5 mm and 2.5 mm. Preferably, the mini-tablets have a curved shape. In one embodiment of the invention, the diameter of the mini-tablets is 1.9-2.1 mm, especially around 2 mm.

The thickness of the mini-tablets can range, for example, from 1 to 3 mm, especially from 1.5 to 2.6 mm, and especially from 1.9 to 2.3 mm, especially around 2 to 2.2 mm.

Active ingredients: In the context of the present invention, the term "sacubitril and valsartan in a 1:1 molar ratio" refers to a therapeutically effective amount of a 1:1 molar ratio of (i) valsartan or a pharmaceutically acceptable salt thereof; and (ii) ) refers to a combination drug containing sacubitril or a pharmaceutically acceptable salt thereof.

Sacubitril is the INN of N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoic acid ethyl ester. It is a prodrug of (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid. Sacubitril can be prepared by known methods, for example, described in US Pat. No. 5,217,996, incorporated herein by reference.

Valsartan is (S)-N-valeryl-N-{[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl]-methyl}-valine. Valsartan or (S)-N-valeryl-N-{[2′-(1H-tetrazol-5-yl)-biphenyl-4-yl]-methyl}-valine, or a pharmaceutically acceptable salt thereof, can be purchased from commercial sources or found, for example, in US Pat. It can be prepared by known methods described. Valsartan may be used in certain embodiments of the invention in its free acid form and in any suitable salt form. Esters or other derivatives of the carboxyl group and salts and derivatives of the tetrazole group may optionally be used.

In one embodiment thereof, the combination comprises a 1:1 molar ratio of (i) valsartan; and (ii) sacubitril or a pharmaceutically acceptable salt thereof, such as the sodium or calcium salt.

In another embodiment thereof, the combination comprises formula (I)
[(A ₁ )(A ₂ )](Na ⁺ ) _y ·xH ₂ O (I)
(In the formula,
A ₁ is valsartan in anionic form;
_A2 is sacubitril in anionic form;
Na ⁺ is a sodium ion;
y is 1-3, preferably 1, 2 or 3;
x is 0 to 3, preferably 0, 0.5, 1, 1.5, 2, 2.5 or 3)
is provided in the form of a compound of

In one embodiment, y is 3 and x is 2.5.

In particular, the compound is trisodium [3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3′-methyl-2′-( Pentanoyl {2″-(tetrazol-5-ylato)biphenyl-4′-ylmethyl}amino)butyrate]hemipentahydrate (LCZ696).

In a preferred embodiment, the compound trisodium [3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3′-methyl-2′- (Pentanoyl{2″-(tetrazol-5-ylato)biphenyl-4′-ylmethyl}amino)butyrate]hemipentahydrate exists in crystalline form.

The corresponding active ingredient or its pharmaceutically acceptable salts may also be used in the form of hydrates or contain other solvents used for crystallization.

Preferably, the compounds Sacubitril or its salts, Valsartan or its salts, or LCZ696 are substantially pure or in substantially pure form. As used herein, "substantially pure" refers to at least about 90% pure, more preferably at least about 95%, and most preferably at least about 98% pure.

Also, these compounds are solid, in solid form, or preferably in a solid state. The solid, solid form or solid state may be crystalline, partially crystalline, amorphous or polyamorphous, preferably in crystalline form.

Amount of Active Ingredient: In one embodiment of the invention there is provided a solid unit dosage form in the form of mini-tablets as described herein above, said mini-tablets comprising between about 2 mg and about 5 mg per mini-tablet, especially Contains an effective amount of active ingredient between about 2.5 mg and about 4.0 mg per mini-tablet, equivalent to a 1:1 molar ratio of valsartan (free acid) and sacubitril (free acid), respectively do. In one preferred embodiment, each mini-tablet contains an amount of 3.125 mg of active ingredient per tablet, just as defined.

In one embodiment, the active ingredient is provided in the form of LCZ696. The effective amount of LCZ696 is based on the weight of the two active ingredients, sacubitril and valsartan, excluding the weight of sodium and bound water contained in the complex, i. LCZ696 in the range of between about 2 mg to about 5 mg per dosage unit, particularly between about 2.5 mg to about 4.0 mg per unit dosage form. In one embodiment of the invention, each mini-tablet contains an amount of 3.125 mg of LCZ696, just as defined. Taking sodium and water of hydration into account, the mini-tablets contain between about 3 mg and about 4 mg, preferably about 3.534 mg of trisodium [3-((1S,3R)-1-biphenyl -4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3′-methyl-2′-(pentanoyl{2″-(tetrazol-5-ylato)biphenyl-4′-ylmethyl}amino ) Butyrate] hemipentahydrate.

Core: The core of the mini-tablet according to the invention comprises at least one pharmaceutically acceptable excipient. Such additives (or additive) are suitable for preparing solid oral dosage forms according to the present invention. Tabletting aids commonly used in tablet formulations can be used, and reference is made to the extensive literature on this subject, particularly Fiedler, "Lexikon der Hilfstoffe," 4th Edition, ECV Aulendorf 1996, and these is incorporated herein by reference. These include, but are not limited to, fillers or excipients, binders, lubricants, fluidizers, stabilizers, surfactants, softeners, pigments, and the like.

In one embodiment, the present invention provides a solid oral formulation comprising a therapeutically effective amount of Sacubitril and Valsartan in a 1:1 molar ratio, especially in the form of LCZ696, and at least one filler (excipient) as an additive substance. Regarding dosage forms. Further additive substances include one or more selected from the group consisting of binders, lubricants, fluidizers (antiblocking agents), stabilizers, surfactants, pigments, softeners, etc. It is not limited to these. The amounts of active ingredient and further additive substances are preferably those defined below.

In another embodiment, the present invention provides a solid oral formulation comprising a therapeutically effective amount of Sacubitril and Valsartan in a 1:1 molar ratio, particularly in the form of LCZ696, and fillers (excipients) and binders as additive substances. Regarding dosage forms. Further optional additive substances include lubricants and one or more, for example two, superplasticizers and optionally one or more stabilizers, surfactants, pigments and softeners. include, but are not limited to. The amounts of active ingredient and further additive substances are preferably those defined herein below.

In a further embodiment, the present invention provides a therapeutically effective amount of Sacubitril and Valsartan in a 1:1 molar ratio, especially in the form of LCZ696, and a filler (excipient), binder, lubricant, and one or more It relates to a solid oral dosage form comprising a plurality of, for example two, flow agents as additive substances. Additional optional additive materials include, but are not limited to, one or more of stabilizers, surfactants, pigments, softeners, and the like. The amounts of active ingredient and further additive substances are preferably those defined herein below.

One or more of these additive substances can be selected and used by those skilled in the art in view of the particular desired properties of the solid oral dosage form through routine experimentation and without any undue burden.

Fillers or excipients include customary additive substances known in the art, such as microcrystalline cellulose (MK GR), powdered sugar, compressible sugar, dextrates, dextrin, dextrose. , lactose, especially anhydrous lactose, mannitol, starches such as potato starch, wheat starch and maize starch; powdered cellulose, sorbitol, sucrose and microcrystalline cellulose; preferably the filler is microcrystalline cellulose , for example products available under the registered trademarks AVICEL, FILTRAK, HEWETEN or PHARMACEL. The most preferred filler is microcrystalline cellulose, especially microcrystalline cellulose having a density of about 0.45 g/cm ³ , such as AVICEL. The filler, especially microcrystalline cellulose, has a density of about 20% to about 60%; for example about 30% to about 50% by weight of the core (before coating), preferably about 40% by weight of the core can exist in

Binders are customary additives known in the art, such as cellulose derivatives, especially hydroxypropylcellulose (HPC), especially hydroxypropylmethylcellulose with a Brookfield viscosity in the range of 100-5000 CPS, eg 300-600 CPS. Hydroxypropyl cellulose (HP cellulose) with a viscosity in the range of The binder, especially HP cellulose, is present in an amount of from about 1% to about 40%, from about 2% to about 20%, from about 3% to about 10%, especially from about 3.5% to about It may be present in a concentration of 5.5%, especially from about 4% to about 5%. Some additives may also be considered disintegrants, but for the purposes of the present invention they are preferably considered binders.

As lubricants , stearic acid and its salts, especially magnesium stearate (Mg), aluminum stearate (Al) or calcium stearate (Ca); glycerol esters, especially PEG 4000 to 8000; hydrogenated castor oil, Na stearyl fumarate, Hydrogenated cottonseed oil and the like can be mentioned. The most preferred lubricants are Mg stearate and/or stearic acid. The amount of lubricant present is from 0.2 to 6% by weight, especially for Mg stearate from 1.0% to 5.0% by weight, for example based on the weight of the core (before coating): It can vary within the range of 1.5% to 3.5%, especially 2.0% to 3.0%.

Glidants can include , inter alia, colloidal silica, such as colloidal silicon dioxide, such as AEROSIL, magnesium trisilicate (Mg), powdered cellulose, starch, talc and tribasic calcium phosphate or combinations thereof. In particular, fluidizing agents can be included in the form of a mixture of these fluidizing agents and fillers or binders, for example silicided microcrystalline cellulose (PROSOLV). The most preferred fluidizing agents are colloidal silicon dioxide (eg AEROSIL 200) and/or talc. AEROSIL® is a trademark of Evonik Industries AG, Darmstadt, Germany. The amount of superplasticizer present is from 0.1 to 5% by weight, such as from 1.5 to 3.5% by weight, especially from 0.5% to 1.0% by weight for talc, colloidal dioxide It may vary from 0.2% to 4.0% by weight for silicon, in particular from 1.0% to 2.0%, based on the weight of the core (before coating).

Therefore, in one embodiment, the solid oral dosage form according to the invention comprises as additive substances a filler, especially microcrystalline cellulose, and a binder, especially hydroxypropylcellulose (HP cellulose).

In one embodiment, the solid oral dosage form according to the present invention comprises binders and lubricants, in particular microcrystalline cellulose, hydroxypropylcellulose and magnesium stearate, in addition to fillers, as additive substances.

In one embodiment, the solid oral dosage form according to the invention comprises, in addition to fillers, binders and lubricants, as additive substances, at least one glidant, especially microcrystalline cellulose, hydroxypropylcellulose, Contains magnesium stearate and colloidal silicon dioxide and/or talc.

It is a characteristic of the present solid oral dosage forms that they contain only relatively small amounts of excipients that provide the desired high content of active ingredient. This requires the manufacture of physically small unit dosage forms. The total amount of additive materials in a given uncoated unit dosage form (i.e., core) is no more than about 70%, more particularly no more than about 60% by weight, based on the total weight of the core before coating. obtain. Preferably, the additive content is in the range of about 40% to 59% by weight, based on the weight of the core before coating, and more particularly the additive content is in the range of about 45% to about It is in the range of 54% by weight. For the total weight of the solid oral dosage form (including core and coating), the total amount of additive materials in the core is no more than about 65% by weight, more particularly no more than about 60%, based on the total weight of the solid oral dosage form. can be Preferably, the additive material content is in the range of about 40% to 55% by weight, based on the weight of the total unit dosage form, and more particularly, the additive material content is in the range of about 55% to It is in the range of about 50% by weight.

Thus, the active ingredient is present in a concentration of 30% to 70%, preferably 40% to 60%, more preferably approximately 50% by weight of the core before any coating.

A preferred amount of filler, especially microcrystalline cellulose, in the tablet core ranges from about 35% to 45%, eg 39% to 41% by weight, each based on the weight of the core before coating.

A preferred amount of binder, especially hydroxypropylcellulose, in the tablet core is 2% to 8%, such as 3.5% to 5.5%, respectively, based on the weight of the core before coating, such as It ranges from 4% to 5% by weight.

A preferred amount of lubricant, especially Mg stearate, in the tablet core is respectively 0.2% to 6.0%, such as 1.0% to 5.0% by weight of the core before coating, such as , in the range from 1.5% to 3.5% by weight, in particular from 2.0% to 3.0% by weight.

A preferred amount of glidant, especially colloidal silicon dioxide and/or talc, in the tablet core is 0.1% to 5.0% by weight, respectively, relative to the content of the total glidant, e.g. It ranges from 1.5% to 3.5%, such as from 1.5% to 2.5% by weight of the core. Specifically, the amount of individual superplasticizer present is between 0.5% and 1.0% by weight of the core weight (before coating) for talc and 0.5% for colloidal silicon dioxide. It ranges from 2 wt% to 4.0 wt%, such as from 1.0 wt% to 2.0 wt%.

In one embodiment, the solid oral dosage form according to the invention comprises, as excipients, microcrystalline cellulose in an amount of 35% to 45% by weight, 2% to 8% by weight, such as 3.5% to 5.5% by weight. Hydroxypropyl cellulose in an amount of wt. %, such as colloidal silicon dioxide in an amount of 1.0% to 2.0% by weight, and talc in an amount of 0.5% to 1.0% by weight, where % is the coating Refers to weight percent relative to the previous core.

In one embodiment thereof, the solid oral dosage form according to the invention comprises as additives microcrystalline cellulose in an amount of 35% to 45% by weight, hydroxypropylcellulose in an amount of 2% to 8% by weight, stearin The acid Mg is present in an amount of 1.0% to 5.0% by weight, the colloidal silicon dioxide is present in an amount of 0.2% to 4.0% by weight, and the talc is present in an amount of 0.5% by weight. It is present in an amount from wt% to 1.0 wt%, where wt% refers to wt% of the core before coating.

In another embodiment thereof, the solid oral dosage form according to the invention comprises, as additives, microcrystalline cellulose in an amount of 35% to 45% by weight and hydroxypropyl in an amount of 3.5% to 5.5% by weight. cellulose, Mg stearate present in an amount of 1.5% to 3.5% by weight, colloidal silicon dioxide present in an amount of 1.0% to 2.0% by weight, talc is present in an amount of 0.5 wt% to 1.0 wt%, where wt% refers to wt% of the core before coating.

Further preferred amounts of LCZ696 and additive materials are shown in illustrative examples.

The absolute amount of each excipient and the amount relative to other excipients will likewise depend on the desired properties of the solid oral dosage form, and can be selected by those skilled in the art through routine experimentation and without undue burden. . For example, a solid oral dosage form can be selected to release the active agent slowly, with or without quantitative control of the release of the active agent, especially in the presence of food added prior to administration to the patient. .

Film-coating: According to the present invention, the core of the mini-tablets described herein is coated with a film-coating with slow-release functionality and/or protective properties, wherein said coating further protects the drug substance. It may help mask taste and thus improve patient compliance. In particular, the film-coating helps control the release of active ingredients, especially LCZ696, in vitro and in vivo, especially since it is already dissolved in food added before use for more convenient drug administration. aim to avoid

In another embodiment, the dissolution rate behavior of mini-tablets is aligned with that of marketed single tablets by modifying the release via the application of a film coating.

Thus, in one embodiment of the invention, the film coating prevents premature release of the drug when mixed with food.

In one embodiment of the present invention, said film coating with sustained release functionality has a pH dependent release profile that allows mixing known (e.g. palatable tasting) food products especially for children prior to administration. have. In particular, preferably the coating only dissolves at a pH of 5 or below, so that dissolution in eg foodstuffs and hence loss of eg flavor masking properties can be prevented. Or, in other words, the film coating is acid soluble up to pH 5.0.

In one embodiment thereof, the solid unit dosage form according to the present invention leads to an equivalent or slower in vitro dissolution of the active ingredient at pH 5.0 or lower as compared to the in vitro dissolution of the active ingredient at pH 6.5 or higher. , has a film coating with a pH-dependent release profile.

Accordingly, in one embodiment, there is provided a solid unit dosage form as described herein, wherein said film coating comprises: Released an amount of valsartan greater than or equal to about 30% (by weight) and Sacubitril greater than or equal to about 25% (by weight) after 10 minutes and about 35% (by weight) after 20 minutes, as measured by the USP paddle method at about 50 rpm. % (by weight) or greater of valsartan and about 30% (by weight) or greater of sacubitril, and after 30 minutes release of greater than or equal to about 40% (by weight) of valsartan and greater than or equal to about 35% (by weight) of sacubitril. suitable for or leading to in vitro dissolution of active ingredients, especially in the form of LCZ696, such as, where % by weight is the active ingredients of the total effective amount of Sacubitril and Valsartan in a molar ratio of 1:1 refers to the weight percent of individual sacubitril and valsartan relative to the weight of

In another embodiment thereof, there is provided a solid unit dosage form as described herein, wherein said film coating comprises: Released an amount of valsartan greater than or equal to about 35% (by weight) and Sacubitril greater than or equal to about 30% (by weight) after 10 minutes and about 40% (by weight) after 20 minutes, as measured by the USP paddle method at about 50 rpm. % (by weight) or more of valsartan and about 35% (by weight) or more of sacubitril, and after 30 minutes an amount of about 45% (by weight) or more of valsartan and about 40% (by weight) or more of sacubitril is released. suitable for or leading to in vitro dissolution of an active ingredient, particularly in the form of LCZ696, as releasing, wherein weight % is the total effective amount of active ingredients in a molar ratio of 1:1 Sacubitril and Refers to weight percent of individual sacubitril and valsartan relative to weight of valsartan.

In another embodiment, there is provided a solid unit dosage form as described herein, wherein said film coating comprises:
- at a pH between about 2 and 4.5, in particular pH 4.5, after 10 minutes, about 35% (by weight) or more, after 20 minutes, about 40% (by weight) or more, after 30 minutes, about releasing more than 45% (by weight) of valsartan, and/or at a pH between about 6 and about 7, especially at pH 6.8, after 10 minutes, less than or equal to about 40% (by weight) after 20 minutes; suitable for or leading to in vitro dissolution of valsartan to release no more than about 45% (by weight) of valsartan after 30 minutes, where no more than about 50% (by weight) of valsartan is released, wherein the weight percent is Refers to the weight percent of individual valsartan relative to the weight of the total effective amount of active ingredients, Sacubitril and Valsartan in a molar ratio of 1:1.

In one embodiment, a test to measure dissolution of an individual active ingredient at neutral pH is performed according to USP <711> using the paddle method at pH 6.8 and 50 rpm, wherein the dissolution medium is , pH 6.8 at 37±0.5° C., 900 mL of 0.05 M phosphate buffer.

In one embodiment, a test to measure the dissolution of an individual active ingredient at neutral pH is performed according to USP <711> using the paddle method at pH 4.5 and 50 rpm, wherein the dissolution medium is , pH 4.5 at 37±0.5° C., 900 mL of 0.05 M phosphate buffer.

In one embodiment, a test to measure dissolution of an individual active ingredient at acidic pH is performed according to US Pharmacopeia <711> using the paddle method at pH 2.0 and 50 rpm, the dissolution medium comprising: 900 mL of 0.01N HCl at pH 2.0, 37±0.5°C.

In one embodiment of the invention, the solid unit dosage form was measured by the USP paddle method at about 50 rpm in 900 mL of 0.05 M phosphate buffer, pH 6.8, 37±0.5° C. In that case, the dissolution profile of a mini-tablet with a loading equivalent to an effective dose of 200 mg active ingredient exhibits an in vitro dissolution profile of the active ingredient that is comparable to the dissolution profile of the marketed LCZ696 200 mg tablet formulation. Said release profile is disclosed in WO2009/061713. Specifically, an oral dosage form at a dosage of 200 mg of therapeutic agent (1:1 molar ratio of sacubitril and valsartan) in 900 mL of 0.05 M phosphate buffer, pH 6.8, at 37±0.5° C. Released about 50% (by weight) or more of valsartan after 10 minutes, released about 85% (by weight) or more of valsartan after 20 minutes, and released 30% (by weight) of valsartan, as measured by the USP paddle method at about 50 rpm. It exhibits an in vitro dissolution profile such that it releases more than about 95% (by weight) of valsartan after 1 minute, where weight % is the effective amount of the active ingredient valsartan in a 1:1 molar ratio of sacubitril and valsartan. Refers to the weight percent of individual valsartan relative to the weight of the portion only. That is, since a 200 mg dose contains 103 mg valsartan and 97 mg sacubitril, this is a USP After 10 minutes, about 26% (by weight) or more of valsartan was released, after 20 minutes, about 44% (by weight) or more of valsartan was released, and after 30 minutes, about 49% (by weight) was released, as measured by the paddle method. weight) of valsartan, where the weight percent is the total effective amount of the active ingredients, sacubitril and valsartan, in a molar ratio of 1:1, with respect to the weight of the individual sacubitril and valsartan. Refers to weight percent of valsartan.

For solid oral dosage forms in the form of film-coated mini-tablets according to the invention, typically polymers such as HPMC, PVP, sugar, shellac, or other films completely conventional in the art. Coatings, most preferably coatings comprising polyacrylates. For example, by known methods using equipment available from Aeromatic, Glatt, Wurster or Huttlin in a perforated pan coater, for example using equipment from Accela Cota, Glatt, Driam or others, or Other methods conventional in the art call attention to the numerous known methods of coating used in the art, such as spray coating in fluidized beds. Additives commonly used in confectionery can be used in this way.

In one embodiment, the present invention provides a solid unit dosage form as described herein, wherein said film coating comprises at least one polyacrylate as a film former.

In a preferred embodiment, the film coating comprises a basic butylated methacrylate copolymer (optionally defined in the European Pharmacopoeia) as film former.

In another embodiment, the present invention provides a solid unit dosage form as described herein, wherein said film coating comprises an ammonium methacrylate copolymer, particularly a Form A ammonium methacrylate copolymer (optionally European Pharmacopeia). ) and/or B-type ammonium methacrylate copolymers (optionally defined in the European Pharmacopoeia) as film formers.

In one embodiment, the polyacrylate is
a) basic butylated methacrylate copolymers formed from monomers selected from butyl methacrylate, (2-dimethylaminoethyl) methacrylate and methyl methacrylate, preferably butyl methacrylate, (2-dimethylaminoethyl)-methacrylate and a 1:2:1 copolymer formed from methyl methacrylate,
b) copolymers formed from monomers selected from methacrylic acid and methacrylic acid lower alkyl esters; and c) ammonio methacrylate copolymers formed from monomers selected from ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate chloride. selected.

In one particular variant, the mini-tablets are made of polyacrylate, preferably Eudragit®, such as Eudragit®-E or Eudragit®-RD100 or -RS/RL (Handbook of Pharmaceutical Excipients, loc. cit. hereafter, p. 362), inter alia coated with Eudragit®-EPO (Eudragit® is a trademark from Evonik Industries AG Kirschenallee, Darmstadt, Germany).

Accordingly, suitable coating materials for the compositions of the present invention include polyacrylic acid polymers, such as:
a) Trademark Eudragit® E, especially Eudragit® E PO (chemical name: poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate; CAS number: 24938-16- 7) 1:2:1 copolymer formed from butyl methacrylate, (2-dimethylaminoethyl)-methacrylate and methyl methacrylate available in 1:2:1);
b) 1:1 copolymers formed from monomers selected from methacrylic acid and methacrylic acid lower alkyl esters, e.g. from methacrylic acid and methyl methacrylate available under the trademark Eudragit® L, e.g. Eudragit® L100 1:1 copolymers formed and 1:1 copolymers of methacrylic acid and acrylic acid ethyl ester available under the trademark Eudragit® L100-55;
c) a 1:2:0.2 copolymer formed from ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate chloride available under the trademark Eudragit® RL; or the counterpart available under the trademark Eudragit® RS or 1:2:0.2 formed from ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate chloride in combination with carboxymethyl cellulose and available under the trademark Eudragit® RD copolymer;
More preferred are those mentioned in a).

The average molecular weight of the polyacrylates mentioned above is preferably respectively about 30,000 to about 500,000, eg about 30,000 g/mol.

Polyacrylates, especially Eudragit® E PO, for example coating with Eudragit® E PO, are not readily soluble at the neutral pH of any food administered by mouth or with, and are predominantly 5 It is particularly suitable for coating solid dosage forms containing LCZ696, as it dissolves at pH values below It has been found that

Coating materials as defined above are, for example, talc, magnesium stearate or stearic acid, or synthetic amorphous silicic acid of the Syloid® type (Grace), such as Syloid® 244FP, silicon dioxide or colloidal silicon dioxide, such as Aerosil®, e.g. Aerosil® 200, and/or wetting agents, such as sodium dodecyl sulfate (sodium lauryl sulfate), e.g. Duponol®, or polyethylene It can be used in admixture with further additives conventional in coating formulations such as glycols or polysorbates.

A particularly preferred composition of the present invention is therefore a coated LCZ696 comprising particles that are, for example, tablets, especially mini-tablets or pellets, wherein the coating is a (taste-masking) polyacrylate coating, preferably contains Eudragit® E or Eudragit RD100®, especially Eudragit® E PO, in the coating magnesium stearate or stearic acid as antiblocking agent, basic butylated methacrylate copolymer, As a film forming agent, sodium lauryl sulfate (Duponol) is used/present as a solubilizer and purified water as a solvent for the coating (which is then removed).

In one embodiment thereof, the solid dosage form of the present invention has a film coating comprising, in addition to the polyacrylate, especially a basic butylated methacrylate copolymer, which is preferably a basic butylated methacrylate copolymer. contains a 1:2:1 copolymer formed from butyl methacrylate, (2-dimethylaminoethyl)-methacrylate and methyl methacrylate, and also sodium lauryl sulfate, stearic acid and talc.

In one embodiment thereof, the coating comprises a basic butylated methacrylate copolymer in an amount of 50% to 70%, preferably 55% to 60% by weight, 20% to 40%, preferably 25% by weight. talc in an amount between 5% and 30% by weight, stearic acid or Mg stearate in an amount between 5% and 10% by weight, preferably between 7.5% and 9% by weight, between 1% and 10% by weight, preferably Contains sodium lauryl sulfate in an amount of 4% to 8% by weight.

In another embodiment, the solid dosage form may comprise an additional coating, which is a layer of non-stick material applied over one of the above coatings comprising a colloidal silicon dioxide product such as Aerosil®. , which may avoid sticking of the solid dosage forms to each other or to the container material, eg the walls of the capsule.

In one embodiment of the invention, the solid dosage form has an amount of film coating of 0.1% to 10%, such as 2.0% to 8.5% by weight of the total dosage form, including core and coating. can vary within a range. A preferred amount of film coating ranges from about 4% to about 8% by weight, representing, for example, about 0.2 mg to 0.4 mg per 7 mg mini-tablet unit.

In another embodiment, the amount of film coating may vary within the range of 0.1-5 mg/cm 2 , such as 0.4 mg/cm ² -0.7 mg/cm ² .

Methods: For the preparation of core tablets containing a therapeutically effective amount of Sacubitril and Valsartan in a molar ratio of 1:1, especially in the form of LCZ696, dry granulation methods, especially roller compaction, can preferably be used. Wet granulation can cause stability problems if it leads to changes in the drug substance.

Dry granulation of LCZ696 using a mixture of dry drug substance and excipients has been found to be the best method of manufacture suitable for solid oral dosage forms of LCZ696 according to the present invention, especially mini-tablets. , showing the following advantages:
Minimal impact on changes in drug substance quality;
• achieve a robust manufacturing process for DP;
• Achieve formulation and process scaling resulting from reproducible DP performance;
• Achieve adequate stability to achieve adequate shelf life.

The additive may be distributed partly in the internal phase of the core (granules) and partly in the external phase of the core, preferably this is the case described in the present invention. Preferably, fillers, especially microcrystalline cellulose, glidants, especially colloidal silicon dioxide, and lubricants, especially Mg stearate, are partly in the internal phase and partly in the external phase; binders, especially Hydroxypropylcellulose, which serves as a binder during granulation, and further fluidizing agents, especially talc, are only part of the internal phase; and only fillers, especially microcrystalline cellulose, fluidizing agents, especially colloidal dioxide. Silicon and lubricants, especially Mg stearate, are present in the outer phase.

Internal phase additives such as fillers, fluidizers, binders and lubricants, and drug substance are mixed and granulated using roller compaction. The granules are sieved. An external phase containing, for example, fillers, glidants and lubricants is sieved and mixed with the granules. The mixture is compressed into mini-tablets. The core is preferably coated with a film coating.

The granule phase is defined as the internal phase and the excipients added to the granules are defined as the external phase of the mixture to be compressed.

The present invention also relates to methods for the preparation of solid oral dosage forms, as hereinbefore described and hereinafter described. Such solid oral dosage forms may be produced by assembling the components defined herein above in appropriate amounts to form unit dosage forms, especially mini-tablets, according to the invention.

Accordingly, the present invention is a process for the manufacture of a solid oral dosage form of the invention comprising:
a) mixing the active ingredient and the additives of the internal phase and dry granulating (especially roller compacting) said components; optionally using an intervening sieving method;
b) mixing the granules with external phase additives;
c) compressing the resulting mixture to form a solid oral dosage form as a core (especially a mini-tablet core), preferably using multiple tip tooling; and d) the resulting core. A method is provided comprising coating a tablet to obtain a film-coated tablet, especially a mini-tablet.

Preferably, the additives of step (a) are selected from fillers, at least one fluidizer, lubricants and binders; and the additives of the external phase of step (b) are fillers, lubricants, selected from lubricants and fluidizers;

The manufacture of granules can be carried out on standard equipment suitable for granulation processes. Manufacture of the final blend and tablet compression can also be performed on standard equipment.

For example, in step (a), the blending can be done by a diffusion mixer (tumble) or bin blender, such as a Bohle container blender or Turbula T10B, with a first sieving, for example, with 0.8 mm round wire/vibrating bar It can be carried out in a screening mill, eg Frewitt, and granulation is carried out using a roller compactor, eg Bepex 200/50, to obtain a granular material, which is then, for example, 1.0 mm instead of 0.8 mm round wire. A separate sieving step may be performed as previously described, but using 0 mm round wires. Step (b) then blends the filler and superplasticizer in a diffusion mixer (tumble) or bin blender, for example using a Turbula T10B or Bohle container blender, followed by, for example, a 0.8 mm hand sieve , adding additional lubricant (after sieving with a 0.8 mm hand sieve for example) and blending in a diffusion mixer (tumble) or bin blender, for example in a Turbula T10B or Bohle container blender. . Step (c) can then be performed using a dry compression method, for example a tablet press such as the Korsch PH250, Korsch XL400 or Fette P1200i. This gives the core.

Mini-tablets are compressed on a standard rotary tablet press with a special multi-tip device. A multi-tip device can consist of, for example, up to 19 tips per punch. Such mini-tablet punches have a larger contact area at the die compared to standard tablet punches. Therefore, particle size distribution and powder flow properties are important to obtain a uniform tablet mass. Formulation lubrication and/or choice of equipment (eg, spray lubrication) play an advantageous role in the manufacturing process.

As described above, the core tablet is then film-coated in step (d) to provide the film-coated (particularly mini) tablets previously described herein. The coating mixture is prepared, for example, by mixing the water-containing ingredients using an agitator such as IKA with a screw agitator and then sieving through, for example, a 0.5 mm hand sieve, such as Aeromatic-Fielder MP1. of the Wurster fixation using a peristaltic pump (e.g. Watson Marlow) and tubing of suitable diameter, for example using a fluidized bed dryer with direct heat, obtained in step (c) The core can then be prepared by coating.

Due to the high water solubility of LCZ696, prolonged contact with water should preferably be avoided to prevent degradation of the drug substance. The coating process typically removes water quickly, thereby preventing long-term contact with LCZ696. Alternatively, applying a process of organic film coating may provide a way to avoid adversely affecting the composite.

Pan drying conditions reduced the high water content in film-coated mini-tablets to overcome the adverse effects and associated challenges of high surface area mini-tablets with less hygroscopic LCZ696. can be changed to This can be achieved by using coating equipment with improved drying conditions, for example a fluidized bed coater.

The coating may also contain pigments, such as iron oxide pigments, titanium dioxide as a coloring agent, or one or more pigments that both enhance the appearance and help identify the composition. obtain. Pigments suitable for use typically include, but are not limited to carotenoids, chlorophyll and lakes.

Uses: The solid oral dosage forms of the present invention are administered to children or to treat or prevent cardiovascular or renal disease, especially heart failure (together with "treatment thereof"). It can be used in the manufacture of a medicament for treatment or prevention (together with "treatment thereof").

The present invention also relates to a method of treatment (including prophylactic treatment) of cardiovascular or renal disease, especially heart failure, in children, especially children aged 0.5 to 17, in need of such treatment. , to a method comprising administering a therapeutically effective solid oral dosage form according to the present invention.

The invention likewise relates to the use of a solid oral dosage form according to the invention for the manufacture of a medicament for the pediatric treatment of cardiovascular or renal disease, in particular heart failure (the term "treatment" includes prophylactic treatment). Regarding.

The present invention likewise relates to a pharmaceutical composition for the pediatric treatment (the term "treatment" includes prophylactic treatment) of cardiovascular or renal disease, in particular heart failure, comprising a solid oral dosage form according to the invention. composition comprising:

Ultimately, the precise dose of active agent and the particular formulation to be administered will depend on several factors, including the condition being treated, the desired duration of treatment and the rate of release of the active agent. For example, known in vitro or It can be determined based on in vivo techniques. Mini-tablets allow easy adaptation of the dosage by simply varying the number of mini-tablets used in administration according to (among other things individual) patient requirements.

The above fully discloses the invention including preferred embodiments thereof. Modifications and improvements of the embodiments specifically disclosed herein are within the scope of the following claims. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. Accordingly, the examples herein are to be construed as illustrative only and not as limiting the scope of the invention.

Study drug: LCZ696:
LCZ696 is a supramolecular complex, trisodium [3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3′-methyl -2′-(Pentanoyl{2″-(tetrazol-5-ylate)biphenyl-4′-ylmethyl}amino)butyrate]hemipentahydrate. This compound and its pharmaceutical compositions have previously been described in International Publication No. 2007/056546 and WO2009/061713, the preliminary teachings of which are incorporated herein by reference.

[Example 1]
Preparation of mini-tablets Batches of 200,000 up to 1,303,142 unit dosage forms (size 2.0 mm, curved film-coated mini-tablets) were manufactured, with each unit dosage , having the following composition, an effective amount of 3.125 mg of Sacubitril and Valsartan in a 1:1 molar ratio (LCZ696 3.534 mg, or a theoretical amount of 3.368 mg of LCZ696 acid anhydride, namely water-free Sacubitril, equivalent to sodium).

Additive:
Cellulose MK GR is microcrystalline cellulose, eg from JRS Pharma, Germany (Vivapur 102) HP cellulose 300-600 CPS is hydroxypropylcellulose, eg from Ashland Specialty, South Park, US Aerosil® ) 200 is colloidal silica (fumed silica) Evonik, Germany.
• Duponol® is sodium lauryl sulphate, eg from tensa Chem, Belgium.
- Basic polymethacrylate E PO refers to Eudragit® E PO, Evonik Germany

The composition of the mini-tablets is set forth in Table 1 below.

Production method:
Step 1: LCZ696, Cellulose MK-GR, Aerosil, HP Cellulose 300-600 CPS, Mg Stearate and Talc are blended for 150 revolutions to obtain a mixture.
Step 2: The resulting mixture is subjected to a sieving step to obtain Premix I.
Step 3: Mix premix I for 100 revolutions to obtain premix II.
Step 4: Premix II is dry granulated (roller compacted).
Step 5: Screen the resulting granules at 1.0 mm.
Step 6: Cellulose MK GR and Aerosil in the outer phase are sieved to 0.8 mm, added to the granules in step 7 and then blended for 100 revolutions.
Step 8: Mg stearate in the external phase is sieved to 0.8 mm and added to the blend obtained after step 7.
Step 9: Blend the mixture from Step 8 for 60 revolutions to obtain the final blend (for tablet cores).
Step 10: Granulate the final blend, resulting in bulk core material.

Use the following tablet press.

Step 11: Mix basic polymethacrylate E PO, stearic acid, Duponol and purified water at 700 rpm.
Step 12: Add talc to the mixture of step 11 and mix the ingredients.
Step 13: The blend obtained in step 12 is sieved, resulting in a film coating suspension that is applied onto the bulk core material from step 10 in a fluidized bed with direct heat by spray coating (e.g. batch Product temperature during coating 28-35° C., use of 1.2 mm nozzle, spray rate 4-8 g/min, spray pressure 1.5 bar) for size 500 g.

"Revolutions" refers to revolutions per minute.

manufacturing device:

The resulting tablets are packaged as subbatches in flat pouches from PETP/Al/PE.

[Example 2]
Mini-tablet dosage form 64 mini-tablets (200 mg total) bottled or either 4 mini-tablets (12.5 mg total) or 10 mini-tablets (31.25 mg total) each provided in a capsule containing These are created to make it easier for subjects/parents/administrators as well as pharmacy staff to administer accurate doses.

[Example 3]
Dissolution Test The tablets of the examples are tested for their dissolution in 900 ml of pH 6.8 phosphate buffer with a paddle of 50 rpm.

The assembly consists of: a lidded container made of glass or other inert transparent material; a motor and a paddle formed from a blade and shaft as a stirrer. The container is partially submerged in a suitable water bath of any convenient size or placed in a heating jacket. A water bath or heating jacket maintains the temperature in the vessel at 37±0.5° and the bath liquid in a constant, smooth motion during the test. No part of the assembly equipment, including the environment in which it is placed, contributes to significant movement, agitation or vibration beyond that of a smoothly rotating stirrer. A device that allows observation of the specimen and stirrer during testing has the following dimensions and capacity: height from 160 mm to 210 mm and internal diameter from 98 mm to 106 mm. Its sides are flanged at the top. A suitable cover may be used to retard evaporation. The shaft is positioned so that its axis is no more than 2 mm from the vertical axis of the container and rotates smoothly without significant wobble. The vertical centerline of the blade passes through the axis of the shaft so that the bottom surface of the blade is flush with the bottom surface of the shaft. The paddle design is as shown in US Pharmacopoeia <711>, FIG. A distance of 25±2 mm between the blade and the inner bottom surface of the container is maintained during the test. A metallic or suitably inert hard blade and shaft constitute one object. A preferred two-piece detachable design may be used provided that the assembly remains tightly engaged during testing. Paddle blades and shafts may be coated with a suitable inert coating. A dosage unit or formulation dosage unit is submerged in the bottom of the container, after which the blades begin to rotate. A small loose piece of non-reactive material, such as no more than the number of turns of a helix of wire, can be attached to an otherwise floating dosage unit. Other effective sinker devices may be used.

A buffered aqueous solution adjusted to pH 6.8 ± 0.05 (dissolve 6.805 g potassium dihydrogen phosphate and 0.896 g sodium hydroxide, dilute to 1000 ml with water, add 0.2 M sodium hydroxide or 1 M phosphoric acid 900 mL of a 0.05 M phosphate buffer solution (hereinafter referred to as "dissolution medium") obtained by adjusting the pH to 6.80 ± 0.05 using Equilibrate the dissolution medium to 37±0.5° and remove the thermometer. One dosage form (eg, tablet or capsule) is placed in the apparatus taking care to remove air bubbles from the surface of the dosage unit and immediately the apparatus is operated at a speed of 50+2 rpm. At specific time intervals (e.g. 10, 20, 30, 45, 60, 90 and 120 minutes), or at each time noted, the sample (>1 ml) was applied to the surface of the dissolution medium and the top of the rotating blade. in the middle, from the part that is more than 1 cm from the wall of the container. [Note - Replace the aliquot removed for analysis with the same volume of fresh dissolution medium at 37°, or correct for volume changes in calculations if it can be shown that no medium replacement is necessary. . The container is covered throughout the test and the temperature of the mixture under test is checked at suitable times. ]. The specimen is filtered through a suitable filter, eg a 0.45 μm PVDF filter (Millipore) and the first few ml (2-3 ml) of the filtrate are discarded. Analysis is performed with HPLC or UV detection. The test is repeated at least 6 times with additional dosage units.

Example tablets are also tested using the method described above at pH 4.5 by performing the method described above and optionally applying the following modifications: Prepare a pH 4.5 phosphate buffer solution. This was accomplished by dissolving 13.61 g of potassium dihydrogen phosphate in 750 ml of water, adjusting the pH with 0.1 M sodium hydroxide or 0.1 M hydrochloric acid if necessary, and diluting to 1000.0 ml with water. do.

Alternate dissolution test conditions at pH 4.5:
Rotation speed, 75±3 rpm; test medium, 900 mL pH 4.5 phosphate buffer solution.

[Reference example] LCZ696 tablet 200 mg
Table 2 below shows formulations for effective doses of 100 mg, 200 mg and 400 mg therapeutic agents (taken from WO 2009/061713, page 18 ff, adjusted).

The manufacturing method is as described in WO 2009/061713 pamphlet, page 20.

[Example 5]
Comparison of Bioavailability Purpose: The purpose of this study was to determine the relative bioavailability of LCZ696 mini-tablets 200 mg compared to the final commercial form of tablets of LCZ696 200 mg under fasting conditions. and to evaluate the effect of food on the bioavailability of LCZ696 mini-tablets 200 mg. To evaluate the food effect of LCZ696, mini-tablets were administered with a tablespoon of pudding or pudding and a high-fat meal.

Study Design: Randomized, open-label, single-dose, crossover study in healthy subjects. Enrollment: 40 subjects; Completion: 39 subjects.

Treatment A : Single oral dose of LCZ696 200 mg FMI

Treatment B : Single oral dose of LCZ696 200 mg in LCZ696 mini-tablets

Treatment C : Single oral dose of LCZ696 200 mg in LCZ696 mini-tablets sprinkled over a tablespoon of pudding

Treatment D : A single oral dose of LCZ696 200 mg in LCZ696 mini-tablets, sprinkled over a tablespoon of pudding and administered with a high-fat meal.

Pharmacokinetics: Statistical analysis of relative bioavailability of mini-tablets compared to FMI tablets, effect of purines, and effect of high-fat diet are presented in Table 4.

Following oral administration of a single oral dose of 200 mg under fasting conditions, the primary PK parameter variables of sacubitril, LBQ657 and valsartan were similar between minitablets and FMI tablets as geometric mean ratios, The 90% CIs corresponding to both C _max and AUC were within 80-125%. T _max values were also similar between these two formulations, suggesting no effect of formulation effect on the rate of absorption.

Similarly, when the 200 mg mini-tablet was administered with a tablespoon of vanilla pudding, the GMR and 90% CI for AUC _last , AUC _inf and C _max for LCZ696 were also within the range of 0.80 to 1.25. , showing no significant effect of small amounts of vanilla pudding on the bioavailability of the mini-tablets. The Tmax values were also similar between these two treatments, suggesting no effect of vanilla pudding on the rate of absorption of the LCZ696 analyte.

When a single dose of LCZ696 200 mg mini-tablets sprinkled over pudding was administered with a high-fat meal, the C _max of sacubitril and LBQ657 were lowered by 60% and 19%, respectively. However, when the GMR and 90% CI on AUC _inf and AUC _last of sacubitril and LBQ657 were within the range of 80-125%, there was no effect of high fat diet. Food delayed the absorption of sacubitril and LBQ657 from mini-tablets by 2.5 and 2 hours, respectively. When LCZ696 mini-tablets were administered with a high-fat meal, the Cmax and AUC of valsartan decreased by 57% and 41%, respectively. The rate of absorption of valsartan was also delayed by 2 hours when LCZ696 mini-tablets were administered with food.

The relative bioavailability of LCZ696 analytes after administration of mini-tablets 200 mg compared to FMI tablets 200 mg, and the effects of purines and high-fat diet on PK exposure with mini-tablets are presented in Table 3.

Conclusions • The rate (Cmax) and extent (AUC) of absorption of LCZ696 analytes were comparable between LCZ696 200 mg mini-tablets and LCZ696 200 mg FMI tablets in healthy subjects under fasting conditions.
• The rate (Cmax) and extent (AUC) of absorption of the LCZ696 analytes were comparable when LCZ696 200 mg mini-tablets were administered with or without a small amount of vanilla pudding.
• When LCZ696 200 mg in LCZ696 mini-tablets sprinkled over pudding was administered with a high-fat meal, the Cmax of AHU377, LBQ657 and Valsartan were lowered by 60%, 19% and 57%, respectively. However, while the extents of absorption (AUC) for AHU377 and LBQ657 were comparable, the extent of absorption (AUC) for valsartan was reduced by about 40%.

The present invention includes the following aspects.
<1>
A mini-tablet for oral administration having a core and an outer coating, comprising:
- said core comprises as active ingredients a therapeutically effective amount of Sacubitril and Valsartan in a molar ratio of 1:1; and at least one pharmaceutically acceptable excipient;
wherein said therapeutically effective amount of active ingredient is between about 2 mg and about 5 mg per mini-tablet, said therapeutically effective amount comprising a 1:1 molar ratio of Sacubitril (free acid) and Valsartan (free acid), respectively. equivalent to the combined amount of
- said outer coating is in the form of a slow release and/or protective film coating,
- be between 1 mm and 4 mm in size,
mini pills.
<2>
The active ingredient is trisodium [3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3'-methyl-2'-( The mini-tablet according to <1>, which is in the form of pentanoyl {2″-(tetrazol-5-ylate)biphenyl-4′-ylmethyl}amino)butyrate]hemipentahydrate (LCZ696).
<3>
<1> or <2>, wherein the diameter is between 1 mm and 3 mm, preferably between 1.5 mm and 2.5 mm, more preferably between 1.9 mm and 2.1 mm, especially around 2 mm mini pills.
<4>
The mini-tablet according to any one of <1> to <3>, containing 3.125 mg of the active ingredient per tablet.
<5>
About 3 mg to about 4 mg per tablet, preferably about 3.534 mg of trisodium [3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S )-3′-methyl-2′-(pentanoyl{2″-(tetrazol-5-ylate)biphenyl-4′-ylmethyl}amino)butyrate]hemipentahydrate, the mini-tablet according to <1> .
<6>
pH dependent release profile wherein said sustained release and/or protective film coating leads to slow in vitro dissolution of the active ingredient at pH 5.0 or lower compared to in vitro dissolution of the active ingredient at pH 6.5 or higher. The mini-tablet according to any one of <1> to <5>.
<7>
When measured by the USP paddle method at about 50 rpm in 900 mL of 0.05 M phosphate buffer at pH 6.8 at 37±0.5° C.
- after 10 minutes, releasing an amount of about 30% (by weight) or more of valsartan and about 25% (by weight) or more of sacubitril,
- after 20 minutes, releasing an amount of about 35% (by weight) or more of valsartan and about 30% (by weight) or more of sacubitril,
- After 30 minutes, release an amount of valsartan greater than or equal to about 40% (by weight) and Sacubitril greater than or equal to about 35% (by weight)
exhibiting an in vitro dissolution profile of the active ingredient such as
Here, weight percent refers to the weight percent of individual sacubitril and valsartan relative to the weight of the total effective amount of active ingredients, sacubitril and valsartan in a molar ratio of 1:1.
The mini-tablet according to any one of <1> to <6>.
<8>
The mini-tablet according to any one of <1> to <7>, wherein the film coating comprises at least one polyacrylate.
<9>
The mini-tablet of <8>, wherein the polyacrylate is a basic butylated methacrylate copolymer formed from monomers selected from butyl methacrylate, (2-dimethylaminoethyl) methacrylate and methyl methacrylate.
<10>
The mini-tablet of <9>, wherein the basic butylated methacrylate copolymer is a 1:2:1 copolymer formed from butyl methacrylate, (2-dimethylaminoethyl)-methacrylate and methyl methacrylate.
<11>
The mini-tablet according to any one of <1> to <10>, wherein the sustained release and/or protective film coating further comprises sodium lauryl sulfate, stearic acid and talc.
<12>
The sustained release and/or protective film coating comprises a basic butylated methacrylate copolymer in an amount from 50% to 70% by weight, talc in an amount from 20% to 40% by weight, and an amount from 5% to 10% by weight. stearic acid or Mg stearate, sodium lauryl sulfate in an amount of 4% to 8% by weight, the mini-tablet according to <11>.
<13>
The mini-tablet according to any one of <1> to <12>, wherein the weight of the sustained release and/or protective film coating is about 4% to about 8% of the total dosage form including core and coating.
<14>
The mini-tablet of any one of <1> to <13>, wherein the core comprises the active ingredient at a concentration of 30% to 70% by weight of the core before any coating.
<15>
(ii) hydroxypropyl cellulose; (iii) Mg stearate, Ca stearate or Al stearate; (iv) anhydrous colloidal silica (colloidal dioxide silicon), and (v) talc.
<16>
Said microcrystalline cellulose is present in an amount of 35% to 45% by weight, hydroxypropyl cellulose is present in an amount of 2% to 8% by weight and Mg stearate is present in an amount of 1.0% to 5.0% by weight. Present in an amount of 0% by weight, colloidal silicon dioxide present in an amount of 1.0% to 2.0% by weight, and talc in an amount of 0.5% to 1.0% by weight. The mini-tablet of <15>, wherein the weight percent refers to the weight percent relative to the core before coating.
<17>
The mini-tablet according to any one of <1> to <16> provided together with a dispenser.
<18>
Contains a specified number of mini-tablets according to any one of <1> to <16>, and the specified number is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19 and 20, preferably containing 4 or 10 mini-tablets.
<19>
A mini-tablet according to any one of <1> to <17> for use in the treatment of diseases or conditions in the pediatric population, particularly in the treatment of heart failure in patients belonging to the pediatric population.
<20>
chronic heart failure, hypertension, angina pectoris, myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiomyopathy, renal failure, peripheral vascular disease, left ventricular hypertrophy, cognitive impairment, and stroke, particularly low A mini-tablet according to any one of <1> to <17>, for use in treatment or prevention in patients who require dose and individual dose administration or who encounter swallowing problems.

Claims (14)

A mini-tablet for oral administration having a core and an outer coating, comprising:
- said core comprises as active ingredients a therapeutically effective amount of Sacubitril and Valsartan in a molar ratio of 1:1; and at least one pharmaceutically acceptable excipient;
The active ingredient is trisodium [3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3'-methyl-2'-( in the form of pentanoyl {2″-(tetrazol-5-ylate)biphenyl-4′-ylmethyl}amino)butyrate]hemipentahydrate,
The therapeutically effective amount of active ingredient is 3.125 mg per mini-tablet, which corresponds to a combined dose of Sacubitril (free acid) and Valsartan (free acid) in a molar ratio of 1:1. and
The pharmaceutically acceptable excipient is
(i) microcrystalline cellulose in an amount of 35% to 45% by weight;
(ii) hydroxypropylcellulose in an amount of 2% to 8% by weight;
(iii) Mg stearate in an amount of 1.0% to 5.0% by weight;
(iv) anhydrous colloidal silica (colloidal silicon dioxide) in an amount of 1.0% to 2.0% by weight;
(v) talc in an amount of 0.5% to 1.0% by weight, wherein said weight% refers to weight% of said core before coating;
- said outer coating is in the form of a slow release and/or protective film coating,
the weight of the sustained release and/or protective film coating is about 4% to about 8% of the total dosage form including the core and coating;
The sustained release and/or protective film coating comprises a basic butylated methacrylate copolymer in an amount from 50% to 70% by weight, talc in an amount from 20% to 40% by weight, and an amount from 5% to 10% by weight. of stearic acid or Mg stearate, sodium lauryl sulfate in an amount of 4% to 8% by weight ,
- the diameter of said mini-tablets is between 1 mm and 3 mm;
mini pills. 2. Mini-tablets according to claim 1, wherein the diameter is between 1.5 mm and 2.5 mm. 2. Mini-tablets according to claim 1, wherein the diameter is between 1.9 mm and 2.1 mm, in particular around 2 mm. pH dependent release profile wherein said sustained release and/or protective film coating leads to slow in vitro dissolution of the active ingredient at pH 5.0 or lower compared to in vitro dissolution of the active ingredient at pH 6.5 or higher. The mini-tablet according to any one of claims 1 to 3, having When measured by the USP paddle method at about 50 rpm in 900 mL of 0.05 M phosphate buffer at pH 6.8 at 37±0.5° C.
- after 10 minutes, releasing valsartan in an amount of about 30% (by weight) or more and Sacubitril in an amount of about 25% (by weight) or more;
- after 20 minutes, releasing valsartan in an amount of about 35% (by weight) or more and Sacubitril in an amount of about 30% (by weight) or more;
- exhibiting an in vitro dissolution profile of said active ingredient such that after 30 minutes an amount of valsartan greater than or equal to about 40% (by weight) and an amount of sacubitril greater than or equal to about 35% (by weight) are released,
Here, weight percent refers to the weight percent of individual sacubitril and valsartan relative to the weight of the total effective amount of active ingredients, sacubitril and valsartan in a molar ratio of 1:1.
A mini-tablet according to any one of claims 1-4. Mini-tablets according to any one of claims 1 to 5, wherein the basic butylated methacrylate copolymer is formed from monomers selected from butyl methacrylate, (2-dimethylaminoethyl) methacrylate and methyl methacrylate. 7. Mini-tablets according to claim 6, wherein the basic butylated methacrylate copolymer is a 1:2:1 copolymer formed from butyl methacrylate, (2-dimethylaminoethyl)-methacrylate and methyl methacrylate. Mini-tablets according to any one of claims 1 to 7, provided with a dispenser. containing a defined number of mini-tablets according to any one of claims 1 to 7, said defined number being 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19 and 20. 10. Capsules according to claim 9 containing 4 or 10 mini-tablets. Mini-tablets according to any one of claims 1 to 7 for use in the treatment of diseases or conditions in the pediatric population. 12. Mini-tablets according to claim 11 for use in the treatment of heart failure in patients belonging to the pediatric population. A mini-tablet according to any one of claims 1 to 7 for use in the treatment or prevention of diseases selected from the group consisting of chronic heart failure, hypertension, angina pectoris and myocardial infarction. 14. Mini-tablets according to claim 13 , for use in patients who require low and discrete dose medications or who encounter swallowing problems.